Study Identifies Gene That Prevents Nerve Cell Death

October 27, 2002

Many neurological diseases occur when specific groups of neurons die because of nerve damage, toxins, inflammation, or other factors. A new study suggests that activity of a single gene can stop neurons from dying regardless of what triggers this process. The findings could lead to new ways of treating neurodegenerative diseases.From the National Institute of Neurological Disorders and Stroke :Study Identifies Gene That Prevents Nerve Cell Death Friday, October 25, 2002

Many neurological diseases occur when specific groups of neurons die because of nerve damage, toxins, inflammation, or other factors. A new study suggests that activity of a single gene can stop neurons from dying regardless of what triggers this process. The findings could lead to new ways of treating neurodegenerative diseases.

“Turning on the gene for heat shock protein 27 (HSP27) could potentially rescue nerve cells in patients with neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS),” says senior author Clifford Woolf, M.D., Ph.D., of Massachusetts General Hospital and Harvard Medical School in Charlestown, Massachussetts. Heat shock proteins are a group of molecules that help protect cells against stress-induced damage. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appeared in the September 26, 2002, issue of Neuron.

Previous studies have shown that sensory and motor neurons from newborn animals die by cell suicide, or programmed cell death, if their axons or nerve fibers are injured. Neurons from adults, however, usually survive after injury. Researchers believe that some cell survival factors are turned off in newly formed neurons because many of these cells must die during normal development. “In the adult, however, the biological need is just the opposite. Cells need a way to protect themselves,” says Dr. Woolf. He and his colleagues set out to learn what protects adult neurons from death.

In the study, Dr. Woolf and his colleagues severed sensory and motor nerves of the peripheral nervous system in newborn and adult rats. The peripheral nervous system carries signals between the central nervous system (the brain and spinal cord) and the rest of the body. The researchers found that HSP27 levels increased rapidly in all injured sensory and motor neurons in the adult rats. In the newborn rats, however, HSP27 increased only in a small number of motor neurons. Those neurons survived, while all of the other injured neurons died.

When the researchers gave newborn rats extra copies of HSP27 genes before a nerve injury, many injured neurons survived. However, when they reduced HSP27 activity by preventing expression of the protein in cultured adult neurons and in adult rats after nerve injury, most of the affected neurons died. The researchers also found that HSP27 interfered with the activity of a protein called caspase-3, which is one of the last steps in the biochemical process that leads to programmed cell death.

These findings may lead to new strategies for preventing or treating ALS and other neurological diseases such as peripheral neuropathy, Dr. Woolf says. “Such disorders may result from a failure to increase the amount of HSP27,” he suggests. Researchers might be able to increase HSP27 activity through gene therapy or by mimicking factors that normally activate the protein.

Because HSP27 interferes with one of the last steps in the process leading to programmed cell death, it may be able to stop the cell death no matter what triggers the process, the researchers suggest.

“HSP27’s role is well-studied in non-neuronal cells, but we have only now begun to appreciate its role in the central nervous system,” Dr. Woolf says. Previous studies of non-neuronal cells with HSP27 activity have shown that these cells are resistant to excessive heat, chemical stress, toxins, and inflammatory proteins. Other studies have linked HSP27 activity to drug resistance in cancer cells.

Researchers recently found that a mouse model for a degenerative motor neuron disease called spinal muscular atrophy has reduced activity of the mouse version of HSP27, Dr. Woolf notes. This reduced protein activity appears to be linked to the death of the motor neurons. Researchers also have linked HSP27 to survival of retinal ganglion neurons, which are part of the central nervous system. This suggests that the protein may influence neuron survival in the brain and spinal cord as well as the rest of the body.

While these findings are promising, they are still preliminary, and it is too soon to begin testing HSP27 in humans, the researchers say. Since HSP27 can allow cancer cells to survive drug treatment, any therapy that alters HSP27 to prevent cell death would need to be studied very carefully to make sure the treated cells do not form drug-resistant tumors, Dr. Woolf points out. He and his colleagues are now planning to test whether the protein can improve the survival of motor neurons in animal models of ALS. They also hope to identify the cellular factors that normally influence HSP27 activity.

The NINDS is a component of the National Institutes of Health in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system.